title: Mitochondria to nucleus translocation of AIF in mice lacking Hsp70 during ischemia/reperfusion.
abstract: Heat shock protein 70 (Hsp70) has been shown to have an anti-apoptotic function, but its mechanism is not clear in heart. In this study, we examined the effect of Hsp70 deletion on AIF-induced apoptosis during ischemia/reperfusion (I/R) in vivo. Although Hsp70 KO and WT mice demonstrated similar amounts of AIF released from mitochondria after I/R surgery, Hsp70 KO mice showed a significantly greater increase in apoptosis, larger infarct size, and decreased cardiac output. There was also a significant fourfold increase in the nuclear accumulation of AIF in Hsp70 KO mice compared with WT mice. Treatment with 4-AN (4-amino-1,8-napthalimide, 3 mg/kg), a potent inhibitor of PARP-1, which is a critical regulator of AIF-induced apoptosis, significantly blocked the release of AIF from mitochondria and the translocation of AIF into the nuclei after I/R in both WT and Hsp70 KO mice. In addition, 4-AN treatment resulted in a significant inhibition of apoptosis, a reduction of infarct size, and attenuated cardiac dysfunction in both WT and Hsp70 KO mice after I/R. The anti-apoptotic function of Hsp70 occurs through the inhibition of AIF-induced apoptosis by blocking the mitochondria to nucleus translocation of AIF. PARP-1 inhibition improves cardiac function by blocking AIF-induced apoptosis.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Sangita
authors.initials: S
authors.lastname: Choudhury
authors.forename: Soochan
authors.initials: S
authors.lastname: Bae
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.forename: Ji Yoo
authors.initials: JY
authors.lastname: Lee
authors.forename: Jacob
authors.initials: J
authors.lastname: Kim
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology
chemical_list: D051033:Apoptosis Inducing Factor; D018840:HSP70 Heat-Shock Proteins; C494830:AIFM1 protein, mouse